Thalamocortical dysconnectivity in autism spectrum disorder: An analysis of the Autism Brain Imaging Data Exchange.
ABSTRACT: Individuals with autism spectrum disorder (ASD) exhibit differences in basic sensorimotor processing as well as general cortical excitability. These observations converge to implicate thalamocortical connectivity as a potential unifying neural mechanism. The goal of this study was to clarify mixed findings on thalamocortical functional connectivity in a large sample of individuals with ASD.Using the Autism Brain Imaging Data Exchange (ABIDE), we examined thalamocortical functional connectivity in 228 individuals with ASD and a matched comparison group of 228 typically developing individuals. In order to fully characterize thalamocortical functional networks, we employed complementary seed-based approaches that examined connectivity of major cortical divisions (e.g. prefrontal cortex, temporal lobe) with the thalamus and whole-brain connectivity of specific thalamic sub-regions.Prefrontal cortex, temporal lobe, and sensorimotor cortex exhibited hyper-connectivity with the thalamus in ASD. In the whole-brain analysis, hyper-connectivity of several thalamic seeds included multiple cortical areas, but tended to converge in temporal cortical areas, including the temporoparietal junction. Follow-up analyses of age effects revealed that the connectivity abnormalities in ASD were more pronounced in adolescents compared to children and adults.These results confirm previous findings of temporal and motor thalamocortical hyper-connectivity in ASD, and extend them to include somatosensory and prefrontal cortex. While not directly addressable with the data available in ABIDE, this widespread hyper-connectivity could theoretically account for sensorimotor symptoms and general cortical excitability in ASD. Future studies should target comprehensive clinical and behavioral characterization in combination with functional connectivity in order to explore this possibility.
Project description:Preliminary evidence suggests aberrant (mostly reduced) thalamocortical (TC) connectivity in autism spectrum disorder (ASD), but despite the crucial role of thalamus in sensorimotor functions and its extensive connectivity with cerebral cortex, relevant evidence remains limited. We performed a comprehensive investigation of region-specific TC connectivity in ASD. Resting-state functional MRI and diffusion tensor imaging (DTI) data were acquired for 60 children and adolescents with ASD (ages 7-17 years) and 45 age, sex, and IQ-matched typically developing (TD) participants. We examined intrinsic functional connectivity (iFC) and anatomical connectivity (probabilistic tractography) with thalamus, using 68 unilateral cerebral cortical regions of interest (ROIs). For frontal and parietal lobes, iFC was atypically reduced in the ASD group for supramodal association cortices, but was increased for cingulate gyri and motor cortex. Temporal iFC was characterized by overconnectivity for auditory cortices, but underconnectivity for amygdalae. Occipital iFC was broadly reduced in the ASD group. DTI indices (such as increased radial diffusion) for regions with group differences in iFC further indicated compromised anatomical connectivity, especially for frontal ROIs, in the ASD group. Our findings highlight the regional specificity of aberrant TC connectivity in ASD. Their overall pattern can be largely accounted for by functional overconnectivity with limbic and sensorimotor regions, but underconnectivity with supramodal association cortices. This could be related to comparatively early maturation of limbic and sensorimotor regions in the context of early overgrowth in ASD, at the expense of TC connectivity with later maturing cortical regions.
Project description:The cerebral cortex and the cerebellum are spatially remote areas that are connected by complex circuits that link both primary and associative areas. Previous studies have revealed abnormalities in autism spectrum disorder (ASD); however, it is not clear whether cortico-cerebellar connectivity is differentially manifested in the disorder. To explore this issue, we investigated differences in intrinsic cortico-cerebellar functional connectivity between individuals with typical development (TD) and those with ASD. To this end, we used functional magnetic resonance imaging (fMRI) of 708 subjects under a resting state protocol provided by the ABIDE I Consortium. We found that people with ASD had diminished functional connectivity between the cerebellum and the following cortical regions: (i) right fusiform gyrus, (ii) right postcentral gyrus, (iii) right superior temporal gyrus, (iv) right middle temporal gyrus, and (v) left middle temporal gyrus. All of these regions are involved in many cognitive systems that contribute to commonly affected functions in ASD. For right fusiform gyrus, right superior temporal gyrus, and left middle temporal gyrus, we reproduced the results in an independent cohort composed of 585 subjects of the ABIDE II Consortium. Our results points toward a consistent atypical cortico-cerebellar connectivity in ASD.
Project description:Autism spectrum disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex, we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as "patches" of mostly increased connection probability or strength in the first postnatal week and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as a possible common pathophysiological substrate of deficits in ASD.
Project description:Recent advanced MRI studies on cervical spondylotic myelopathy (CSM) revealed alterations of sensorimotor cortex, but the disturbances of large-scale thalamocortical systems remains elusive. The purpose of this study was to characterizing the CSM-related thalamocortical disturbances, which were associated with spinal cord structural injury, and clinical measures.A total of 17 patients with degenerative CSM and well-matched control subjects participated. Thalamocortical disturbances were quantified using thalamus seed-based functional connectivity in two distinct low frequencies bands (slow-5 and slow-4), with different neural manifestations. The clinical measures were evaluated by Japanese Orthopaedic Association (JOA) score system and Neck Disability Index (NDI) questionnaires.Decreased functional connectivity was found in the thalamo-motor, -somatosensory, and -temporal circuits in the slow-5 band, indicating impairment of thalamo-cortical circuit degeneration or axon/synaptic impairment. By contrast, increased functional connectivity between thalami and the bilateral primary motor (M1), primary and secondary somatosensory (S1/S2), premotor cortex (PMC), and right temporal cortex was detected in the slow-4 band, and were associated with higher fractional anisotropy values in the cervical cord, corresponding to mild spinal cord structural injury.These thalamocortical disturbances revealed by two slow frequency bands inform basic understanding and vital clues about the sensorimotor dysfunction in CSM. Further work is needed to evaluate its contribution in central functional reorganization during spinal cord degeneration.
Project description:Resting-state functional magnetic resonance imaging (rsfMRI) studies reveal a complex pattern of hyper- and hypo-connectivity in children with autism spectrum disorder (ASD). Whereas rsfMRI findings tend to implicate the default mode network and subcortical areas in ASD, task fMRI and behavioral experiments point to social dysfunction as a unifying impairment of the disorder. Here, we leverage a novel Bayesian framework for whole-brain functional connectomics that aggregates population differences in connectivity to localize a subset of foci that are most affected by ASD. Our approach is entirely data-driven and does not impose spatial constraints on the region foci or dictate the trajectory of altered functional pathways. We apply our method to data from the openly shared Autism Brain Imaging Data Exchange (ABIDE) and pinpoint two intrinsic functional networks that distinguish ASD patients from typically developing controls. One network involves foci in the right temporal pole, left posterior cingulate cortex, left supramarginal gyrus, and left middle temporal gyrus. Automated decoding of this network by the Neurosynth meta-analytic database suggests high-level concepts of "language" and "comprehension" as the likely functional correlates. The second network consists of the left banks of the superior temporal sulcus, right posterior superior temporal sulcus extending into temporo-parietal junction, and right middle temporal gyrus. Associated functionality of these regions includes "social" and "person". The abnormal pathways emanating from the above foci indicate that ASD patients simultaneously exhibit reduced long-range or inter-hemispheric connectivity and increased short-range or intra-hemispheric connectivity. Our findings reveal new insights into ASD and highlight possible neural mechanisms of the disorder.
Project description:Abnormalities in cortical connectivity and evoked responses have been extensively documented in autism spectrum disorder (ASD). However, specific signatures of these cortical abnormalities remain elusive, with data pointing toward abnormal patterns of both increased and reduced response amplitudes and functional connectivity. We have previously proposed, using magnetoencephalography (MEG) data, that apparent inconsistencies in prior studies could be reconciled if functional connectivity in ASD was reduced in the feedback (top-down) direction, but increased in the feedforward (bottom-up) direction. Here, we continue this line of investigation by assessing abnormalities restricted to the onset, feedforward inputs driven, component of the response to vibrotactile stimuli in somatosensory cortex in ASD. Using a novel method that measures the spatio-temporal divergence of cortical activation, we found that relative to typically developing participants, the ASD group was characterized by an increase in the initial onset component of the cortical response, and a faster spread of local activity. Given the early time window, the results could be interpreted as increased thalamocortical feedforward connectivity in ASD, and offer a plausible mechanism for the previously observed increased response variability in ASD, as well as for the commonly observed behaviorally measured tactile processing abnormalities associated with the disorder.
Project description:Autism spectrum disorders (ASD) represent a complex group of neurodevelopmental conditions characterized by deficits in communication and social behaviors. We examined the functional connectivity (FC) of the default mode network (DMN) and its relation to multimodal morphometry to investigate superregional, system-level alterations in a group of 22 adolescents and young adults with high-functioning autism compared to age-, and intelligence quotient-matched 29 healthy controls. The main findings were that ASD patients had gray matter (GM) reduction, decreased cortical thickness and larger cortical surface areas in several brain regions, including the cingulate, temporal lobes, and amygdala, as well as increased gyrification in regions associated with encoding visual memories and areas of the sensorimotor component of the DMN, more pronounced in the left hemisphere. Moreover, patients with ASD had decreased connectivity between the posterior cingulate cortex, and areas of the executive control component of the DMN and increased FC between the anteromedial prefrontal cortex and areas of the sensorimotor component of the DMN. Reduced cortical thickness in the right inferior frontal lobe correlated with higher social impairment according to the scores of the Autism Diagnostic Interview-Revised (ADI-R). Reduced cortical thickness in left frontal regions, as well as an increased cortical thickness in the right temporal pole and posterior cingulate, were associated with worse scores on the communication domain of the ADI-R. We found no association between scores on the restrictive and repetitive behaviors domain of ADI-R with structural measures or FC. The combination of these structural and connectivity abnormalities may help to explain some of the core behaviors in high-functioning ASD and need to be investigated further.
Project description:OBJECTIVE:The objective of this study was to determine whether functional connectivity of the amygdala is altered in preschool-age children with autism spectrum disorder (ASD) and to assess the clinical relevance of observed alterations in amygdala connectivity. METHOD:A resting-state functional connectivity magnetic resonance imaging study of the amygdala (and a parallel study of primary visual cortex) was conducted in 72 boys (mean age 3.5 years; n = 43 with ASD; n = 29 age-matched controls). RESULTS:The ASD group showed significantly weaker connectivity between the amygdala and several brain regions involved in social communication and repetitive behaviors, including bilateral medial prefrontal cortex, temporal lobes, and striatum (p < .05, corrected). Weaker connectivity between the amygdala and frontal and temporal lobes was significantly correlated with increased autism severity in the ASD group (p < .05). In a parallel analysis examining the functional connectivity of primary visual cortex, the ASD group showed significantly weaker connectivity between visual cortex and sensorimotor regions (p < .05, corrected). Weaker connectivity between visual cortex and sensorimotor regions was not correlated with core autism symptoms, but instead was correlated with increased sensory hypersensitivity in the visual/auditory domain (p < .05). CONCLUSION:These findings indicate that preschool-age children with ASD have disrupted functional connectivity between the amygdala and regions of the brain important for social communication and language, which might be clinically relevant because weaker connectivity was associated with increased autism severity. Moreover, although amygdala connectivity was associated with behavioral domains that are diagnostic of ASD, altered connectivity of primary visual cortex was related to sensory hypersensitivity.
Project description:Background:Over the course of the last 30 years, autism spectrum disorder (ASD) diagnoses have increased, thus identifying a large group of aging individuals with ASD. Currently, little is known regarding how aging will affect these individual's neuroanatomy, compared to the neurotypical (NT) population. Because of the anatomical overlap of ASD-related cortical pathology and age-related cortical thinning, both following an anterior-to-posterior severity gradient, we hypothesize adults with ASD will show larger age-related cortical thinning than NT adults. Methods:We analyzed cortical measurements using available data from the multi-site Autism Brain Imaging Data Exchange I (ABIDE I; n=282) and our own cohort of middle-age to older adults with and without ASD (n=47) mostly available in ABIDE II (n=35). We compared correlations between cortical measures and age in right-handed adults with ASD (n=157) and similar NT adults (n = 172), controlling for IQ and site. Participants were 18 to 64 years of age (mean=29.8 years; median=26 years). Results:We found significant differences between diagnosis groups in the relationship between age and cortical thickness for areas of left frontal lobe (pars opercularis), temporal lobe (inferior gyrus, middle gyrus, banks of the superior temporal sulcus, and entorhinal cortex), parietal lobe (inferior gyrus), and lateral occipital lobe. For all areas, adults with ASD showed a greater negative correlation between age and cortical thickness than NT adults. Conclusion:As hypothesized, adults with ASD demonstrated exacerbated age-related cortical thinning, compared to NT adults. These differences were the largest and most extensive in the left temporal lobe. Future longitudinal work is warranted to investigate whether differences in brain age trajectories will translate to unique behavioral needs in older adults with ASD.
Project description:Previous functional connectivity studies have found both hypo- and hyper-connectivity in brains of individuals having autism spectrum disorder (ASD). Here we studied abnormalities in functional brain subnetworks in high-functioning individuals with ASD during free viewing of a movie containing social cues and interactions. Twenty-six subjects (13 with ASD) watched a 68-min movie during functional magnetic resonance imaging. For each subject, we computed Pearson's correlation between haemodynamic time-courses of each pair of 6-mm isotropic voxels. From the whole-brain functional networks, we derived individual and group-level subnetworks using graph theory. Scaled inclusivity was then calculated between all subject pairs to estimate intersubject similarity of connectivity structure of each subnetwork. Additional 54 individuals (27 with ASD) from the ABIDE resting-state database were included to test the reproducibility of the results. Between-group differences were observed in the composition of default-mode and ventro-temporal-limbic (VTL) subnetworks. The VTL subnetwork included amygdala, striatum, thalamus, parahippocampal, fusiform, and inferior temporal gyri. Further, VTL subnetwork similarity between subject pairs correlated significantly with similarity of symptom gravity measured with autism quotient. This correlation was observed also within the controls, and in the reproducibility dataset with ADI-R and ADOS scores. Our results highlight how the reorganization of functional subnetworks in individuals with ASD clarifies the mixture of hypo- and hyper-connectivity findings. Importantly, only the functional organization of the VTL subnetwork emerges as a marker of inter-individual similarities that co-vary with behavioral measures across all participants. These findings suggest a pivotal role of ventro-temporal and limbic systems in autism.